The ongoing research on DNA-protein interactions involves the use of restriction endonucleases and the corresponding methylases as the protein component and well defined oligonucleotides and competitive inhibitors as the DNA Component, has generated exciting possibilities for further work. Endonucleases HpaI and HpaII have been isolated in homogeneous form and their catalytic and physical properties have been studied. In addition, the corresponding methylases have been isolated and their catalytic properties have been investigated. Using chemically synthesized oligonucleotides, interaction of HpaI with the recognition sequence has been determined. These studies show that 5-methyl group of thymidine and 2-amino group of guanine are important contact points for the enzyme. Using different sets of oligonucleotides and HpaII and MspI endonucleases, we have studied the mechanism by which restriction endocnucleases interact with the DNA substrate. On the basis of these studies, a general model for endonucleases cleavage of single strand and duplex DNA has been proposed.